Adult: For symptomatic treatment in patients with normal sinus rhythm and heart rate ≥70 bpm: As an alternative or adjunct to β-blockers: Initially, 2.5-5 mg bid. Increase dose up to a Max of 7.5 mg bid after 3-4 weeks if necessary and if the resting heart rate remains >60 bpm. Titrate downwards to as low as 2.5 mg bid if resting heart rate falls persistently <50 bpm or if symptoms related to bradycardia occur (e.g. dizziness, fatigue, hypotension). Elderly: ≥75 years Initially, 2.5 mg bid. Increase dose if necessary.
Oral Chronic heart failure with reduced ejection fraction
Adult: In patients with NYHA class II to IV heart failure with LVEF ≤35% who are in sinus rhythm with resting heart rate ≥70 bpm: As an alternative to β-blockers or adjunct to standard therapy: Initially, 5 mg bid. Assess patient 2 weeks after treatment initiation and dose may be adjusted to achieve a resting heart rate of 50-60 bpm. Increase dose up to a Max of 7.5 mg bid if the resting heart rate is persistently >60 bpm. Titrate downwards by 2.5 mg bid if the resting heart rate falls persistently <50 bpm or if symptoms related to bradycardia occur (e.g. dizziness, fatigue, hypotension). Dosage and treatment recommendations may vary among countries and individual products (refer to specific product guidelines). Elderly: ≥75 years Initially, 2.5 mg bid. Increase dose if necessary.
Oral Heart failure due to dilated cardiomyopathy
Child: ≥6 months In patients who are in sinus rhythm with elevated heart rate: Patients weighing <40 kg: As oral solution: Initially, 0.05 mg/kg bid. Assess patient every 2 weeks and adjust the dose by 0.05 mg/kg as tolerated to target at least 20% reduction in heart rate. Max dose (age-dependent): 6 months to <1 year 0.2 mg/kg bid; ≥1 year 0.3 mg/kg bid, up to a total of 7.5 mg bid. If bradycardia develops, reduce the dose to the previous dose; in patients who develop bradycardia at the initial dosage, consider reducing dose to 0.02 mg/kg bid. Patients weighing ≥40 kg: As tab or oral solution: Initially, 2.5 mg bid. Assess patient every 2 weeks and adjust the dose by 2.5 mg as tolerated to target at least 20% reduction in heart rate. Max: 7.5 mg bid. If bradycardia develops, reduce the dose to the previous dose. Treatment recommendations may vary among countries and individual products (refer to specific product guidelines).
Should be taken with food. Avoid excessive consumption of grapefruit juice.
Contraindications
Unstable or acute decompensated heart failure, acute MI, cardiogenic shock, congenital QT syndrome; sick sinus syndrome, sinoatrial block, 3rd-degree AV block, unstable angina, severe hypotension (<90/50 mmHg); resting heart rate <70 bpm prior to treatment. Patient dependent on pacemaker (heart rate maintained exclusively by the pacemaker). Severe hepatic impairment (Child-Pugh class C). Pregnancy, lactation, and women of childbearing potential who are not using effective contraception. Concomitant use with strong CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone) or certain moderate CYP3A4 inhibitors with heart rate-reducing properties (diltiazem and verapamil).
Special Precautions
Patient with retinitis pigmentosa, 1st-degree AV block, bundle branch block, ventricular dyssynchrony, mild to moderate hypotension, NYHA class IV heart failure. Not recommended in patients with 2nd-degree AV block, atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function. Patient taking other moderate CYP3A4 inhibitors (e.g. fluconazole). Severe renal (CrCl <15 mL/min) and moderate hepatic impairment. Children.
Adverse Reactions
Significant: Bradycardia, sinus arrest, heart block, atrial fibrillation, luminous phenomena in the visual field (phosphenes). Blood and lymphatic system disorders: Eosinophilia. Cardiac disorders: Ventricular extrasystoles, palpitations, supraventricular extrasystoles. Ear and labyrinth disorders: Vertigo. Eye disorders: Blurred vision. Gastrointestinal disorders: Nausea, diarrhoea, constipation. Investigations: Increased blood creatinine, QT interval prolongation, uncontrolled blood pressure. Metabolism and nutrition disorders: Hyperuricaemia. Nervous system disorders: Headache, dizziness. Musculoskeletal and connective tissue disorders: Muscle cramps. Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Patient Counseling Information
This drug may cause visual disturbances, if affected, do not drive or operate machinery. Women of childbearing potential must use an effective birth control method during treatment.
Monitoring Parameters
Monitor heart rate before initiating treatment, before increasing dose, or after decreasing dose; blood pressure. Regularly monitor cardiac rhythm to assess for atrial fibrillation.
Overdosage
Symptoms: Severe and prolonged bradycardia. Management: Symptomatic and supportive treatment. Administer IV β-stimulating agents (e.g. isoprenaline) if bradycardia with poor haemodynamic tolerance occurs. Administration of IV fluids and atropine may also be considered. May institute temporary cardiac electrical pacing if necessary.
Drug Interactions
Reduced plasma concentration with CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin). May exacerbate QT prolongation with CV QT-prolonging drugs (e.g. quinidine, sotalol, amiodarone) and non-CV QT-prolonging agents (e.g. pimozide, pentamidine). May increase the risk of arrhythmia with K-depleting diuretics (e.g. thiazide and loop diuretics). Potentially Fatal: Increased serum concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, ritonavir, nefazodone), diltiazem and verapamil, which may be associated with risk of excessive bradycardia.
Food Interaction
Food delays absorption but increases exposure by 20-40%. Increased serum concentration with grapefruit juice. Decreased serum concentration with St. John's wort.
Action
Description: Mechanism of Action: Ivabradine is a heart rate-lowering agent. It selectively and specifically inhibits the funny-current (If) in cardiac pacemaker cells, thus reducing the spontaneous pacemaker activity of the sinoatrial node and ultimately reducing heart rate with no effect on myocardial contractility or ventricular repolarisation. Pharmacokinetics: Absorption: Rapidly and almost completely absorbed. Food delays absorption by approx 1 hour and increases the plasma exposure by 20-40%. Absolute bioavailability: Approx 40%. Time to peak plasma concentration: Approx 1 hour (fasting state); approx 2 hours (with food). Distribution: Plasma protein binding: Approx 70%. Metabolism: Extensively metabolised in the intestines and liver via oxidation by CYP3A4 isoenzyme into its major active metabolite, N-desmethyl-ivabradine, which is also metabolised by CYP3A4. Excretion: Via urine (approx 4% as unchanged drug) and faeces. Plasma elimination half-life: 2 hours.
Chemical Structure
Ivabradine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 132999, Ivabradine. https://pubchem.ncbi.nlm.nih.gov/compound/Ivabradine. Accessed Oct. 27, 2023.
Storage
Store between 15-30°C. Protect from light (oral solution).
C01EB17 - ivabradine ; Belongs to the class of other cardiac preparations.
References
Anon. Ivabradine. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 09/03/2023.Anon. Ivabradine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/03/2023.Buckingham R (ed). Ivabradine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/03/2023.Coralan 5 mg and 7.5 mg Film-coated Tablets (Servier Malaysia Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 26/05/2023.Corlanor Tablet, Film Coated; Corlanor Solution (Amgen Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 09/03/2023.Ivabradine Crescent 7.5 mg Film-coated Tablets (Crescent Pharma Limited). MHRA. https://products.mhra.gov.uk. Accessed 09/03/2023.Joint Formulary Committee. Ivabradine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/03/2023.
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